Adaptation of Published Heritable Thrombophilia Testing Guidelines into

Local PracticeTyler Smith, PGY-5, UBC Hematopathology

Supervisor: Dr. A. LeeCollaborators: Dr. D. Pi, Dr. M. Hudoba

2011 CADTH Symposium

Outline

• Heritable thrombophilia testing (HTT)

• Limitations

• Volume and cost

• Guideline adaptation process

• VGH protocol on inpatient HTT

• Survey of local thrombosis experts

• Future directions

Background

• Thrombophilia = “clot loving” (Greek)

• Factors predisposing to thrombosis can be:

• Inherited

• Acquired = ↑ age, immobility, trauma, surgery, pregnancy, estrogens, cancer, PNH, HIT, APLAS, and more...

Heritable Thrombophilia Testing (HTT)

• Five well-recognized inherited thrombophilias:

• Factor V Leiden mutation

• Prothrombin 20210A mutation

• Protein C deficiency

• Protein S deficiency

• Antithrombin deficiency

HT: Magnitude of Risk• Divided into low and high risk groups

Heit, J. ASH Hematology 2007. 127

Gen. Pop. Incident VTE Recurrent VTEThrombophilia Prevalence Prevalence Rel. Risk Prevalence Rel. Risk

Factor V Leiden

3-7% 12-20% 4.3 (1.9-9.7)

40-50% (1.0

Prothrombin G20210A

1-3% 3-8% 1.9 (0.9-4.1)

15-20% (0.9

Protein S Deficiency

0.01-1% 1-3% 32.4 (16.7-62.9)

5-10%

Protein C Deficiency

0.02-0.05% 2-5% 11.3 (5.7-22.3)

5-10%

Antithrombin Deficiency

0.02-0.04% 1-2% 17.5 (9.1-33.8)

2-5%

Limitations of HTT

• Negative results do not exclude heritable causes

• Negative results do not indicate a low risk of recurrent thrombosis

• Acquired factors, but NOT inherited factors, are strong, independent predictors of recurrent VTE

• Family history and clinical features are better at determining risk of thrombosis

Limitations of HTT

• Testing is expensive ($250/patient in BC)

• Unselected HTT is not cost-effective1

• Assays are not standardized and are technically challenging to perform

• Test results are difficult to interpret

• Unclear how results should alter treatment

• Knowing the heritable thrombophilia status has not been shown to improve patient outcomes

HTT Indications

VERY controversial topic in the literature

• “there are no absolute indications for clinical diagnostic thrombophilia testing”1

A small 2009 survey submitted to BC thrombosis experts (10/12 = hematologists) found:

• 82% felt that HTT results influence patient management in <10% cases

• 73% sometimes order HTT even when they don’t think it will influence management

HTT Contraindications

• NOT very controversial topic in the literature

• HTT results are unreliable in patients:

• With acute thrombosis

• On anticoagulant therapy

• HTT is not useful in predicting arterial clots

HTT: Magnitude of the Problem

Volume of HTT at VGHFVL tests performed at VGH April 2005 - March 2009

~2000 tests/year= ~$500K/year!

Our Synopsis of the Problem

• HTT is an area of confusion and overutilization

• Cost to the system is sufficient to warrant intervention to limit inappropriate HTT

HTT: Possible Solutions

Policy vs. Guideline

• Policy = compliance is mandatory

• More likely to encounter resistance

• Guideline = compliance not enforced

• More likely to be educational

HTT Guidelines

• May 2009 meeting of BC hematologists and hematopathologists

• Consensus that there is a need for a set of clear, local (BC) guidelines for HTT to help:

• Establish accepted indications for HTT

• Clarify HTT interpretation

• Limit HTT to situations in which the results are likely to alter management, thereby reducing wasteful testing

Guidelines: Barriers• Resources: time, effort, cost

• Disagreements amongst experts

• Each expert takes their own “biopsy” of the body of literature!

• Need to raise clinician awareness of guidelines

• Resistance to uptake by clinicians

• Perceived threat to autonomy

• Format not “user-friendly”

Guideline Models

Traditional approach

• Evidence-based

• Consensus-based (all stakeholders)

• Consensus-based (experts)

• Expert opinion

Modern approach = blend of evidence and consensus, involving local experts and stakeholders

Bias Expense,Time

Guideline Adaptation

A rigorous, systematic methodology in which existing guidelines are used to ‘create’ locally relevant guidelines

Reduces duplications of effort to achieve efficiency while maintaining the validity of recommendations

Fosters local ownership of guideline recommendations to promote utilization

Useful as a vehicle for inter-provincial collaboration

ADAPTE Collaboration

• An international collaboration of researchers and guideline developers who aim:

• To promote the development and use of clinical practice guidelines through the adaptation of existing guidelines

• To develop and validate a generic adaptation process that will foster valid and high-quality adapted guidelines as well as the users’ sense of ownership of the adapted guideline.

www.adapte.org

Our Objectives

• To implement a local policy and guideline to reduce inappropriate HTT for the inpatient setting

• To adapt published guidelines for the outpatient setting with input from BC experts and stakeholders using ADAPTE framework

Methodology (1)

• For inpatient HTT at VGH:

• Consulted with VGH hematologists

• Created flow chart and pre-printed order (PPO) form for HTT

• Instituted as policy (i.e. HTT not performed without PPO)

• Collected data on who is ordering HTT

Methodology (2)

• Following ADAPTE process:

• Searched Pubmed for HTT guideline set with balanced summary of literature

Brit J Haem (2010) 149(2): 209–20.

Methodology (3)

• ADAPTE: External review by target audience

• transformed BJH 2010 HTT Guidelines into a survey questionnaire

• Survey emailed to BC experts to gather consensus on individual recommendations

• Each recommendation scored on 5-point Likert scale:

• +2 = strongly agree, +1 = agree, 0 = neutral, -1 = disagree, -2 = strongly disagree, N/A

• Mean score used to determine consensus

• 1.00-2.00 = strong, 0.50-0.99 = moderate, 0.00-0.50 = poor, <0.00 = none

Project Results

Effect on Inpatient HTT

PPO Instituted

HTT Guideline BC Survey

• Issued by email July 20, 2010

• Closed Aug 31, 2010

• 20 of 31 specialists participated in survey

• 16 adult hematologists (of 19)

• 1 pediatric hematologist (of 1)

• 2 hematopathologists (of 7)

• 1 general internist (of 1)

HTT Survey Results

• Consensus scoring results:

• Strong = 15/30 (50%) recommendations

• Moderate = 10/30 (33%) recommendations

• Poor = 5/30 (17%) recommendations

• Overall, 25/30 (83%) moderate or strong consensus

HTT Survey Results

• Strong consensus was seen for statements with strong evidence (level 1A or 1B) and weaker consensus for areas with weaker evidence

0

2

4

6

8

10

12

14

Nu

mb

er o

f S

tate

men

ts

Grade 1A or 1BGrade 2B or 1CGrade 2C or C

Strong Moderate Poor

Project Limitations• Most input from adult hematologists, but need

to involve stakeholders (i.e. the people who order most HTT!)

Project Limitations

• Unable to measure impact on patient outcome

• Requires dedicated leadership and content expertise

• Does not address ongoing monitoring of scientific advancement and update of guidelines

Future Directions

Future Plans

• Our ultimate goal is to develop BC practice guidelines by adapting the British guideline recommendations that had moderate or strong consensus

• To maximize acceptance and utilization, we will:

• Obtain feedback on a draft document from highvolume users (e.g. GPs)

• Review feedback and revise as appropriate

• Develop user-friendly tools that will help users to apply these guidelines in their busy practice

Future PlansArrange stakeholder panel to review these guidelines and user-friendly tools

• Must include representation from hematology, family medicine, internal medicine, obstetrics, & neurology

Seek guideline partnership or endorsement with Guidelines and Protocols Advisory Committee (GPAC)

• Currently, the Clinical Practice Committee is reviewing HTT ordering patterns of GPs

Publish survey results and guidelines (BCMJ)

Conclusions

• HTT is expensive and has limited clinical utility

• A combination approach by using policy and guideline adaptation best addresses usage patterns in different settings

• Our project demonstrates that cost savings from optimal test utilization can be realized without significant resource costs

• Further work is required to meet our objectives and address current limitations

Acknowledgments

• Dr. Agnes Lee: Supervisor

• Dr. David Pi: Inspiration, VGH HTT data

• Dr. Monika Hudoba: VGH HTT forms

• Dr. Bakul Dalal: GPAC planning

• Dr. George Browman: Guideline adaptation

• Jason Pal: Excel spreadsheets

• And all survey participants...

Sample Guidelines

In counseling women with prior VT regarding oral contraception, one should recommend considering an alternative contraceptive or transdermal HRT without

offering HT testing, as a negative test result does not exclude an increased risk of VT.

In counseling women with a first degree relative with unprovoked VT and a high risk HT (i.e. deficiency of AT, PC, PS) regarding oral contraception, HT testing may assist

VT risk assessment and contraceptive recommendations.

In counseling women with a first degree relative with unprovoked VT and a low risk HT (i.e. FVL or PTGM) regarding oral contraception, one should recommend

considering an alternative contraceptive or transdermal HRT without offering HT testing, as a negative test result does not exclude an increased risk of VT.

In counseling a woman with a first degree relative with unprovoked VT and either negative or unknown HT status regarding oral contraception, one should suggest she consider alternative contraception or transdermal HRT and that HTT is not indicated.

Guide to Heritable Thrombophilia Testing (HTT) in Women Considering Estrogen-Containing Oral Contraceptive Pill Therapy

Sample Guidelines

HTT Indications

• VERY controversial topic in the literature

• “there are no absolute indications for clinical diagnostic thrombophilia testing”1

• “idiopathic or recurrent thrombosis...young age (< 40 years)...positive family history... thrombosis in unusual vascular territory”1

• “unprovoked VTE at any age”2

1. Heit, J. ASH Hematology 2007. 127

HTT in Inpatients

Functional assays for PS, PC, and AT deficiencies are influenced by numerous factors

• Anticoagulants, acute clot, vitamin K deficiency, DIC, liver disease, pregnancy, and others…

Abnormal results lead to repeat testing and mislabeling of patients

VGH Inpatient HTTApril 2005 - March 2009

Total Patients

(N)

Below Normal (Mild)*(N)

Below Normal(Marked)* (N)

LackConfounding Conditions**(N)

AT 245 28 3 1

PC 278 26 16 3

Mildly abnormal results - AT (0.5-0.75), PC (0.5-0.7). Markedly abnormal results: AT (<0.5), PC (<0.5).

** Confounding Conditions - additional laboratory test profile suggestive of a concurrent clinical conditions (anticoagulant therapy, liver disease etc.) which could have caused the low test results.

VGH Inpatient HTT: Who’s Ordering?